S-adenosylmethionine (SAMe) serves as the methyl-group donor in numerous methyltransferase reactions involving proteins, phospholipids, DMAand catecholamines. Widely available as an over-the-counter dietary supplement, it is promoted as a treatment for depression, osteoarthritis and liver disease. Studies indicate that SAMe is not associated with any serious adverse effects. However, because of its role in the methylation cycle and metabolism to homocysteine (Hey), there is concern that SAMe may influence blood total Hey (tHcy) concentrations. Furthermore, SAMe is a potent activator of the enzyme cystathionine synthetase, which acts to remove Hey. The effects of SAMe on Hey metabolism are not clear, especially in subjects with hyperhomocysteinemia. In these subjects with impaired metabolism of Hey, oral administration of SAMe may either worsen the hyperhomocysteinemia or aid in the removal of Hey. Since elevated blood tHcy is a known risk factor for vascular disease, it is important to understand the effect that SAMe supplementation may have on Hey metabolism. An additional mechanism of vascular toxicity exists with SAMe supplementation through increased methylation of proteins that give rise to asymmetric dimethylarginine (ADMA), a potent inhibitor of nitric oxide synthetase implicated in endothelial dysfunction. We therefore propose a double-blind trial to determine the effect of SAMe on blood tHcy in human subjects with mild to moderate hyperhomocysteinemia(>14 umol/L). The specific aims of the study are: 1) To determine the effect of oral SAMe (1200 mg/day) on plasma tHcy; 2) to determine the effect of oral SAMe with and without supplementation of folate, vitamin B12 and B6, on plasma tHcy; 3) to determine the effect of oral SAMe on plasma levels of ADMA. In a forth aim we will study the effect of exogenous administartion on Hey and ADMA metabolism and VEGF secretion in HepG2 cells and HUVEC. This study is important to better understand and assess the benefit to risk of SAMe supplementation.